1. Field of the Invention
The present invention generally relates to the treatment of ischemic conditions of major organs in the human body by promoting growth of collateral vessels to increase blood flow to the target organs and tissues. More specifically, the invention relates to peptide based angiogenic compositions, methods and devices for treating cardiovascular disease associated with reduced blood flow arising from narrowing of a native blood vessel or occlusion of a bypass graft.
2. Description of Related Art
In the United States, cardiac failure due to underlying coronary heart disease is currently one of the leading causes of death. At the present time, coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA) are the most widely used interventions for treating advanced cardiac disease. In CABG, an autologous vessel is used to bypass the area of coronary obstruction or occlusion and to restore the blood flow. In PTCA, a catheter device is employed to unblock the clogged blood vessel to restore adequate blood flow to the heart and a metal stent is usually implanted to maintain vessel patency. Both of those procedures are considered to be highly invasive, are associated with a certain incidence of restenosis, and may not be appropriate for every patient in need of relief from coronary vessel obstructions—particularly when the patient is elderly or has undergone a previous CABG or PTCA procedure. Moreover, in peripheral vascular disease, when the vessels that supply blood to the legs, intestines and other areas of the body experience atherosclerotic narrowing, neither procedure may be an option because of the small size of the occluded peripheral vessels.
In some individuals, blood vessel occlusion is partially compensated by the spontaneous process of angiogenesis, or new vessel growth, in which new collateral vessels form over a period of time to provide natural bypasses around the occluded vessels. The process of angiogenesis generally involves basement membrane degradation and endothelial cell migration and proliferation to form capillaries which may develop further into mature vessels. Naturally occurring mitogenic factors released from lymphoid and endothelial cells can induce angiogenesis and promote neovascularization of damaged or blood starved tissue. The newly formed vessels can oftentimes supplement or entirely replace the function of the impaired vessels, thereby restoring blood flow to the deprived tissue served by the occluded vessels.
Some individuals are unable to generate sufficient collateral vessels to adequately compensate for diminished blood flow to the ischemic tissue. Therefore, a third treatment approach, still in development, endeavors to induce or enhance the growth of new blood vessels around an area of obstruction to restore adequate blood flow to the heart or other blood deprived tissue. Induced or promoted angiogenesis is believed by many investigators to offer the least invasive way to treat coronary heart disease, to be suitable for use in a large percentage of the patient population (including in particular some patients who are not candidates for either CABG or PTCA), and applicable for neovascularization of both myocardial and peripheral tissues.
Several angiogenic agents have recently been identified that promote angiogenesis through either direct attraction and/or induction of proliferation of endothelial cells, or indirect action by stimulating other cell types (e.g., mast cells or macrophages) that, in turn, produce angiogenic factors. Examples of these agents include vascular endothelial growth factor (VEGF), osteonectin or SPARC, basic fibroblast growth factor (bFGF), angiogenin, endothelial growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factor-alpha (TGF-α), transforming growth factor-beta (TGF-β), and tumor necrosis factor-alpha (TNF-α). Each of these angiogenic agents or factors are either synthetic, meaning that they are manufactured chemically from non-living sources, or are produced by recombinant manufacturing processes (Freedman, S. B., and Isner, J. M., Therapeutic angiogenesis for ischemic cardiovascular disease, J. Mol. Cell Cardiol 33(3): 379-393 (2001)).
Another angiogenic agent, disclosed in co-assigned U.S. Pat. No. 6,211,157 (Benedict et al./Sulzer Biologics, Inc.), is a bone-derived angiogenic protein (BDAP) mixture that provides a more robust angiogenic response than many single factors such as bFGF or VEGF.
Many approaches to enhancement of localized angiogenesis and/or wound healing involve introduction of an extracellular matrix-like material that can serve as a support or scaffold at the desired site and with which the target cells may interact, usually via specific cell surface receptors, to promote cell proliferation. Extracellular matrix (“ECM”) is the structurally stable material beneath the epithelia surrounding the cells of the connective tissue and constitutes a sort of natural scaffolding material. ECM can also be defined as the macromolecular components of connective tissue, generally consisting of proteoglycans, polysaccharides and proteins, which have major roles in cell shape, cell migration and differentiation, and control of cell growth. A subset of the ECM family of proteins is the adhesion proteins. The two major adhesion proteins, fibronectin and laminin, are involved in many cellular processes, including tissue repair, embryogenesis, blood clotting, and cell migration/adhesion. Accordingly, various studies directed at providing a favorable cellular environment to promote cell proliferation involve fibronectin or particular fibronectin peptides. Many of those studies employ the Arg-Gly-Asp or RGD sequence, which is part of the cell binding domain of fibronectin (see, e.g., U.S. Pat. No. 5,677,276 (Dickerson et al.), and S. L. Schor et al., J Cell Sci 109:2581-2590 (1996)).
Recently, it has been reported that the isoleucine-glycine-aspartic acid (Ile-Gly-Asp or IGD) tripeptide sequence, a component of the fibronectin type I module, can induce cell migration of dermal fibroblasts (S. L. Schor et al., J. Cell Sci 112:3879-3888 (1999)). Biological activity has not previously been ascribed to the conserved IGD motif in fibronectin, although previous studies have implicated the ninth type I repeat, which contains the IGDS (SEQ ID NO:5) sequence, in the assembly of an extracellular fibronectin matrix (M A Chernousov et al., J Biol Chem 266:10851-10858 (1991)). In PCT Published Application No. WO 99/02674 (Schor et al./University of Dundee), certain IGD-containing peptides were described and the IGDS peptide was shown to increase fibroblast migration and vessel number under certain conditions in a rat wound healing model.
While significant advancements have been made in identifying and understanding various modulators of cellular migration and angiogenesis, there remains a pressing need for effective means to promote angiogenesis at ischemic sites in the body, such as the heart and tissues fed by the peripheral vascular system, to restore circulation to blood deprived organs and tissues affected by atherosclerotic disease.